Background: Discordant findings between multiparametric magnetic resonance imaging (mpMRI) and transrectal image-guided biopsies of the prostate (TRUS-P) may result in inadequate risk stratification of localized prostate cancer. Objective: To assess transperineal image-guided biopsies of the index target (TPER-IT) in terms of disease reclassification and treatment recommendations. Design, setting, and participants: Cases referred for suspicion or treatment of localized prostate cancer were reviewed in a multidisciplinary setting, and discordance was characterized into three scenarios: type I-negative biopsies or International Society of Urological Pathology (ISUP) grade 1 cancer in Prostate Imaging Reporting and Data System (PI-RADS) 4 index target (IT); type II-negative biopsies or ISUP grade 1 cancer in anterior IT; and type III-<3 mm stretch of cancer in PI-RADS 3 IT. Discordant findings were characterized in 132/558 (23.7%) patients after TRUS-P. Of these patients, 102 received reassessment TPER-IT. Outcome measurements and statistical analysis: The primary objective was to report changes in treatment recommendations after TPER-IT. Therefore, cores obtained by primary TRUS-P and TPER-IT were analyzed in terms of cancer detection, ISUP grade, and Cambridge Prognostic Group classification using descriptive statistics. Results and limitations: TPER-IT biopsies that consisted of fewer cores than the initial TRUS-P (seven vs 14, p < 0.0001) resulted in more cancer tissue materials for analysis (56 vs 42.5 mm, p = 0.0003). As a result, 40% of patients initially considered for follow-up (12/30) and 49% for active surveillance (30/61) were reassigned after TPER-IT to surgery or intensity-modulated radiotherapy.